EP2536454B1 - Autoinjector with a delay mecanism - Google Patents

Description

Technical Field
• The invention relates to an auto-injector according to the preamble ofclaim 1.
Background of the Invention
• Administering an injection is a process which presents a number of both mental and physical risks and challenges for users and healthcare professionals.
• Injection devices (i.e. devices capable of delivering medicaments from a medication container) typically fall into two categories - manual devices and auto-injectors.
• In a manual device - the user must provide the mechanical energy to drive the fluid through the needle. This is typically done by some form of button / plunger that has to be continuously pressed by the user during the injection. There are numerous disadvantages to the user from this approach. If the user stops pressing the button / plunger then the injection will also stop. This means that the user can deliver an underdose if the device is not used properly (i.e. the plunger is not fully pressed to its end position). Injection forces may be too high for the user, in particular if the patient is elderly or has dexterity problems.
• The extension of the button/plunger may be too great. Thus, it can be inconvenient for the user to reach a fully extended button. The combination of injection force and button extension can cause trembling / shaking of the hand which in turn increases discomfort as the inserted needle moves.
• Auto-injector devices aim to make self-administration of injected therapies easier for patients. Current therapies delivered by means of self-administered injections include drugs for diabetes (both insulin and newer GLP-1 class drugs), migraine, hormone therapies, anticoagulants etc.
• Auto-injectors are devices which completely or partially replace activities involved in parenteral drug delivery from standard syringes. These activities may include removal of a protective syringe cap, insertion of a needle into a patient's skin, injection of the medicament, removal of the needle, shielding of the needle and preventing reuse of the device. This overcomes many of the disadvantages of manual devices. Injection forces / button extension, hand-shaking and the likelihood of delivering an incomplete dose are reduced. Triggering may be performed by numerous means, for example a trigger button or the action of the needle reaching its injection depth. In some devices the energy to deliver the fluid is provided by a spring.
• US 2002/0095120 A1 discloses an automatic injection device which automatically injects a pre-measured quantity of fluid medicine when a tension spring is released. The tension spring moves an ampoule and the injection needle from a storage position to a deployed position when it is released. The content of the ampoule is thereafter expelled by the tension spring forcing a piston forward inside the ampoule. After the fluid medicine has been injected, torsion stored in the tension spring is released and the injection needle is automatically retracted back to its original storage position.
• WO 2004/054645 A2 discloses an injection device including a housing for containing a syringe having a bore extending from an end surface, a needle communicating with the bore through the end surface and a dispensing piston movable in said bore towards said end surface so as to expel the contents of the syringe through the needle, the housing having an opening at one end through which the needle may extend, a resilient member for biassing the syringe and the needle inwardly off the housing, a first coupling element moveable towards said one end so as to move the needle of the syringe out of the opening and to move the dispensing piston of the syringe towards the end surface, a mechanism operable to release the syringe such that the needle moves inwardly off the housing,; a drive coupling for extending from said first coupling element to the dispensing piston of the syringe so as to transfer movement of said first coupling element to the dispensing piston wherein the mechanism is triggered to release the syringe and includes components to delay release of the syringe until a predetermined period after being triggered such that it can be ensured that the dispensing piston reaches the end surface before the syringe is released and/or the mechanism includes an inertial mass moveable with the first coupling element and drive coupling and a release member actuable by the inertial mass to release the syringe such that when the dispensing piston releases the end surface of the syringe and the first coupling element and drive coupling stop moving, the inertial mass continues to move so as to actuate the release member to release the syringe.
• FR 2 905 273 A1 discloses an apparatus for the automatic injection of a product into an injection site, the apparatus comprising:
• a container comprising an open proximate end and a substantially closed distal end and being intended to accommodate the product, and provided at its distal end with an injection needle providing an outlet port of the container,
• a housing intended to accommodate, at least partially, the container, the container being movable relative to that housing between an initial position, in which the needle is contained inside the housing, an insertion position, spaced in a distal way compared to the initial position and in which the needle is exposed over a predetermined length, and an end position in which the needle is contained inside the housing,
• holding means, arranged to maintain the container in the insertion position,
• disabling means, arranged to release automatically the holding means and to make move the container until the end position, the apparatus furthermore including:
• timing means, arranged to control the release of the holding means by the disabling means until substantially all the product contained inside the container was brought to cross the outlet port and the injection needle before the container moves to the end position.
• WO 03/097133 A1 discloses an injection device having a needle which, when the device is operated, is first caused to project, then liquid is forced out through it, and finally the needle is automatically retracted. The needle extends forwardly from a capsule that can slide longitudinally within a barrel-like body, a relatively weak spring normally maintaining the capsule and needle retracted. A more powerful spring acts oppositely on a plunger formed by rod parts which, when released, shoots the capsule forward by acting on the liquid therein, and then forces the liquid out through the projecting needle. At the end of the forward stroke the plunger and capsule are decoupled and the weak spring returns the exhausted capsule and its needle to the retracted position. A lost motion connection provided by a piston of the rod part acts as a damper in a cylinder of the rod part, to ensure that the full dose is ejected from the needle before decoupling occurs.
• WO 2009/141219 A1 discloses a damper for a medicament delivery device, which device comprises a container containing medicament, a stopper arranged in said container and movable for expelling said medicament through a dose delivery means, a plunger rod having opposing proximal and distal ends and capable of acting on said stopper, and force means capable of exerting a force on said plunger rod, wherein said damper comprises a tubular sleeve having opposing proximal and distal ends; said sleeve comprises a compartment formed by a closed end wall at the proximal end of the sleeve and the proximal end of the plunger rod which is positioned in an open end at the distal end of the sleeve; and wherein said compartment comprises a sealable and resilient pad, a fluid, and at least one passage for expelling said fluid in an annular space between said sleeve and an inner wall of said container, thereby creating a dampening force, upon movement of said plunger rod.
Summary of the Invention
• It is an object of the present invention to provide an improved auto-injector.
  The object is achieved by an auto-injector according toclaim 1.
• Preferred embodiments of the invention are given in the dependent claims.
• In the context of this patent application the term proximal refers to the direction pointing towards the patient during an injection while the term distal refers to the opposite direction pointing away from the patient.
• According to the invention a delay mechanism is applied in an auto-injector for administering a dose of a liquid medicament, the auto-injector comprising:
• an elongate housing arranged to contain a syringe with a hollow needle and a stopper for sealing the syringe and displacing the medicament, the housing having a distal end and a proximal end with an orifice intended to be applied against an injection site, wherein the syringe is slidably arranged with respect to the housing,
• driving means capable of, upon activation:
  • pushing the needle from a covered position inside the housing into an advanced position through the orifice and past the proximal end,
  • operating the syringe to supply the dose of medicament, and
  • retracting the syringe with the needle into the covered position after delivering the medicament,
• the component in the shape of a retraction sleeve, axially movably arranged in the housing, with the delay box arranged for slowing down motion of the retraction sleeve in distal direction,
• at least one latch for axially fixing the retraction sleeve in a maximum proximal position,
• a decoupling member arranged to decouple the latch when being moved in proximal direction nearly into a maximum proximal position, thus allowing the retraction sleeve to move in distal direction and retract the needle,
• at least one aperture arranged in the retraction sleeve allowing a respective decoupling arm of the decoupling member to be flexed outward.
• The latches are arranged to be disengaged by the decoupling member before the stopper has reached a maximum proximal position in the syringe when moved in proximal direction. The apertures are arranged to meet the decoupling arms after the stopper has reached its maximum proximal position by means of the motion of the retraction sleeve. A gap is provided between a front face of the retraction sleeve and a syringe holder in their respective maximum proximal positions. The syringe is arranged for joint axial movement with the syringe holder. The gap is arranged to allow the retraction sleeve to travel a distance before retracting the syringe holder so the syringe holder is retracted after the decoupling arms met the apertures.
• According to the invention the delay mechanism for slowing down motion of the retraction sleeve in axial direction of the auto-injector comprises a circumferential outer wall with a back collar attached to the housing and a circumferential inner wall with a front collar attached to the retraction sleeve wherein a cavity is defined between the outer wall and inner wall, the cavity sealed by the back collar against the inner wall and by the front collar against the outer wall, the cavity filled with a viscous fluid, wherein at least one orifice is arranged in the delay mechanism for allowing the viscous fluid, e.g. silicone grease to be pushed out as the volume of the cavity decreases due to axial motion of the component with respect to the housing.
• This is a particularly simple and cost-efficient way to damp the axial motion of the retraction sleeve. The delay mechanism may be applied for slowly starting the motion of the retraction sleeve in one direction while another part, e.g. the stopper is allowed to finish moving in the opposite direction with respect to the retraction sleeve, in particular when the motion of the retraction sleeve is supposed to be triggered by the stopper reaching a predefined position.
• Reliably triggering the retraction of the syringe and needle at the end of an injection normally has to be traded off against an incompletely emptied syringe, which is undesirable. Due to manufacturing tolerances of the syringe and stopper the exact position of the stopper at the end of its travel is not repeatable. Consequently, in some cases the stopper will prematurely bottom out so the retraction will not be triggered at all. In other cases the retraction will be triggered before the stopper bottomed out so residual medicament remains in the syringe.
• Releasing the retraction sleeve from the housing a certain amount of time or travel before the stopper bottoms out in the syringe avoids the risk of stalling the retraction by the stopper hitting the end of the syringe prematurely. The damped backward motion of the retraction sleeve due to the delay mechanism allows the plunger and stopper to finish their forward travel so the syringe is entirely emptied. The apertures of the retraction sleeve and the decoupling arms, which are now moving in opposite directions, meet after the stopper and plunger have stopped in order to decouple the decoupling member from the plunger. Due to the gap between the front face and the syringe holder the retraction sleeve is not immediately dragging the syringe back in distal direction when starting to move back. When the retraction sleeve has travelled back far enough to close the gap the stopper has already bottomed out and the plunger has been decoupled from the decoupling member. As soon as the gap is closed the syringe holder, the syringe, the hollow needle and the plunger are dragged back in distal direction.
• Thus both problems are solved, reliably retracting the hollow needle to a safe position and fully emptying the syringe which is particularly desirable with expensive drugs. Emptying the syringe is also important for dosage accuracy.
• According to the invention a circumferential shoulder is arranged between two portions of at least one of the inner wall and the outer wall with the two portions having different cross sections. Thus the cavity is sealed by the respective collar only until the collar reaches the shoulder. When the collar has
  travelled past the shoulder the cavity is rendered untight so the motion of the component continues undamped from this point, e.g. after the part has finished its travel in the opposite direction.
• When the delay box is provided with the aforementioned shoulder the retraction motion may be continued undamped after stopper has bottomed out and the decoupling member has been decoupled from the plunger in order to speed up the retraction so the needle rapidly disappears in the housing and risk for needle stick injuries is further reduced.
• Preferably the driving means is arranged as a spring means, wherein activating means are arranged to lock the spring means in a pressurized state prior to manual operation and capable of, upon manual operation, releasing the spring means for injection.
• The spring means may be a single compression spring arranged to be grounded at a distal end in the housing for advancing the needle and for injecting the dose of medicament. The force of the compression spring is forwarded to the needle and/or the syringe via a plunger. The compression spring is arranged to have its ground in the housing switched to its proximal end for retracting the syringe when the injection of the medicament is at least nearly finished.
• The single compression spring is used for inserting the needle, fully emptying the syringe and retracting the syringe and needle to a safe position after injection. Thus a second spring for withdrawing the syringe and needle, which is a motion with an opposite sense compared to advancing the syringe and injecting the dose, is not required. While the distal end of the compression spring is grounded the proximal end moves the syringe forward for inserting the needle and carries on to the injection by pushing on the stopper. When the injection is at least nearly finished the compression spring bottoms out at its proximal end, resulting in the proximal end being grounded in the housing. At the same time the distal end of the compression spring is released from its ground in the housing. The compression spring is now pulling the syringe in the opposite direction.
• The auto-injector has a particularly low part count compared to most conventional auto-injectors. The use of just one compression spring reduces the amount of metal needed and consequently reduces weight and costs.
• The compression spring may be arranged inside the retraction sleeve with its distal end bearing against a distal end face of the retraction sleeve and with its proximal end bearing against a thrust face of a decoupling member. The decoupling member is arranged to decouple the latch when being moved in proximal direction nearly into a maximum proximal position. When decoupled the retraction sleeve is allowed to move in distal direction and retract the needle by means of the spring force which is no longer grounded at its distal end.
• At least two resilient decoupling arms are arranged at the decoupling member. The decoupling arms exhibit inner ramped surfaces bearing against a first shoulder of the plunger in proximal direction. The resilient decoupling arms are supportable by an inner wall of the retraction sleeve in order to prevent the decoupling arms from being flexed outward and slip past the first shoulder. In this state the plunger may be pushed in proximal direction by the decoupling member pushing against the first shoulder in order to insert the needle and inject the dose. At least one aperture is arranged in the retraction sleeve allowing the decoupling arms to be flexed outward by the first shoulder thus allowing the first shoulder to slip through the decoupling arms in proximal direction. This may happen when the injection is at least nearly finished. The decoupled plunger allows the syringe and needle to be retracted since it is no longer bearing against the decoupling member.
• The syringe may be arranged for joint axial movement with a syringe holder which is slidably arranged in the retraction sleeve. The syringe holder is provided with at least two resilient syringe holder arms arranged distally, the syringe holder arms having a respective inclined surface for bearing against a second shoulder, which is arranged at the plunger proximally from the first shoulder. The syringe holder arms are supportable by an inner surface of the housing in order to prevent them from being flexed outward. Thus, when the trigger button is pressed the spring force forwarded by the plunger does not yet press against the stopper but against the syringe for forwarding it. Consequently, a so called wet injection is avoided, i.e. the liquid medicament is not leaking out of the hollow needle before the needle is inserted. A widened portion is provided in the housing for allowing the syringe holder arms to flex outwards when the syringe holder has nearly reached a maximum proximal position thus allowing the second shoulder to slip through the syringe holder arms and to switch load of the compression spring from the syringe to the stopper. This allows for defining the moment to start injecting the medicament.
• A stud may be arranged at the distal end of the plunger. The retraction sleeve may have two or more resilient arms distally from the end face for holding the stud. The stud and/or the resilient arms have ramp features. Thus the resilient arms may be pushed apart by the stud when the plunger is moved in proximal direction. The activating means comprise a trigger button arranged at the distal end of the auto-injector. The trigger button is axially moveable and has at least two rigid retainers for preventing the resilient arms from being flexed outward when the trigger button is in a maximum distal position. Upon pushing the trigger button in proximal direction the retainers are moved in proximal direction in a manner to allow the resilient arms to be flexed out by the stud biased by the compression spring in proximal direction. Thus the stud is allowed to slip past the resilient arms in proximal direction under load of the compression spring in order to start a needle insertion/injection/retraction cycle. The main advantages of this trigger mechanism are its simplicity, the low part count and a high reliability.
• In order to reduce the risk of unintentionally triggering the auto-injector a safety button may be arranged laterally at the housing. The safety button has an interlock for preventing the trigger button from being pushed. The safety button is arranged to pull the interlock outward when operated thus allowing the trigger button to be pushed. For this purpose the safety button may be pivoted in the housing or it may be cast in one piece with the housing in a manner to be pivoted somewhere in the middle so pushing one end inwards causes the other end to be pulled outwards.
• Consequently, in order to operate the trigger button the safety button has to be pushed first so the auto-injector cannot be operated unintentionally. Another advantage of the lateral safety button is that the risk of operating the auto-injector in the wrong orientation and injecting into the thumb is reduced.
• Usually the hollow needle is equipped with a protective needle shield for keeping the needle sterile and preventing it from being mechanically damaged. The protective needle shield is attached to the needle when the auto-injector or the syringe is assembled.
• Preferably a cap is provided at the proximal end of the housing. A sheet metal clip is attached to the cap for joint axial movement and independent rotation. The sheet metal clip is arranged to extend through an orifice into the housing when the cap is attached to the housing. The sheet metal clip comprises at least two barbs snapped into a circumferential notch or behind a shoulder of the protective needle shield. This allows for automatically engaging the sheet metal clip with the protective needle shield during assembly. When the cap is removed from the housing in preparation of an injection the protective needle shield is reliably removed without exposing the user too high a risk to injure himself.
• The cap may be attachable to the housing by a screw connection. This allows for a low force removal of the protective needle shield.
• The housing may have at least one viewing window for inspecting the syringe.
• The auto-injector may preferably be used for subcutaneous or intra-muscular injection, particularly for delivering one of an analgetic, an anticoagulant, insulin, an insulin derivate, heparin, Lovenox, a vaccine, a growth hormone, a peptide hormone, a proteine, antibodies and complex carbohydrates.
• The term "medicament", as used herein, means a pharmaceutical formulation containing at least one pharmaceutically active compound,
  wherein in one embodiment the pharmaceutically active compound has a molecular weight up to 1500 Da and/or is a peptide, a proteine, a polysaccharide, a vaccine, a DNA, a RNA, a antibody, an enzyme, an antibody, a hormone or an oligonucleotide, or a mixture of the above-mentioned pharmaceutically active compound,
  wherein in a further embodiment the pharmaceutically active compound is useful for the treatment and/or prophylaxis of diabetes mellitus or complications associated with diabetes mellitus such as diabetic retinopathy, thromboembolism disorders such as deep vein or pulmonary thromboembolism, acute coronary syndrome (ACS), angina, myocardial infarction, cancer, macular degeneration, inflammation, hay fever, atherosclerosis and/or rheumatoid arthritis,
  wherein in a further embodiment the pharmaceutically active compound comprises at least one peptide for the treatment and/or prophylaxis of diabetes mellitus or complications associated with diabetes mellitus such as diabetic retinopathy,
  wherein in a further embodiment the pharmaceutically active compound comprises at least one human insulin or a human insulin analogue or derivative, glucagon-like peptide (GLP-1) or an analogue or derivative thereof, or exedin-3 or exedin-4 or an analogue or derivative of exedin-3 or exedin-4.
• Insulin analogues are for example Gly(A21), Arg(B31), Arg(B32) human insulin; Lys(B3), Glu(B29) human insulin; Lys(B28), Pro(B29) human insulin; Asp(B28) human insulin; human insulin, wherein proline in position B28 is replaced by Asp, Lys, Leu, Val or Ala and wherein in position B29 Lys may be replaced by Pro; Ala(B26) human insulin; Des(B28-B30) human insulin; Des(B27) human insulin and Des(B30) human insulin.
• Insulin derivates are for example B29-N-myristoyl-des(B30) human insulin; B29-N-palmitoyl-des(B30) human insulin; B29-N-myristoyl human insulin; B29-N-palmitoyl human insulin; B28-N-myristoyl LysB28ProB29 human insulin; B28-N-palmitoyl-LysB28ProB29 human insulin; B30-N-myristoyl-ThrB29LysB30 human insulin; B30-N-palmitoyl- ThrB29LysB30 human insulin; B29-N-(N-palmitoyl-Y-glutamyl)-des(B30) human insulin; B29-N-(N-lithocholyl-Y-glutamyl)-des(B30) human insulin; B29-N-(ω-carboxyheptadecanoyl)-des(B30) human insulin and B29-N-(ω-carboxyheptadecanoyl) human insulin.
• Exendin-4 for example means Exendin-4(1-39), a peptide of the sequence H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2.
• Exendin-4 derivatives are for example selected from the following list of compounds:
• H-(Lys)4-des Pro36, des Pro37 Exendin-4(1-39)-NH2,
• H-(Lys)5-des Pro36, des Pro37 Exendin-4(1-39)-NH2,
• des Pro36 [Asp28] Exendin-4(1-39),
• des Pro36 [IsoAsp28] Exendin-4(1-39),
• des Pro36 [Met(O)14, Asp28] Exendin-4(1-39),
• des Pro36 [Met(O)14, IsoAsp28] Exendin-4(1-39),
• des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39),
• des Pro36 [Trp(O2)25, IsoAsp28] Exendin-4(1-39),
• des Pro36 [Met(O)14 Trp(02)25, Asp28] Exendin-4(1-39),
• des Pro36 [Met(O)14 Trp(02)25, IsoAsp28] Exendin-4(1-39); or
• des Pro36 [Asp28] Exendin-4(1-39),
• des Pro36 [IsoAsp28] Exendin-4(1-39),
• des Pro36 [Met(O)14, Asp28] Exendin-4(1-39),
• des Pro36 [Met(O)14, IsoAsp28] Exendin-4(1-39),
• des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39),
• des Pro36 [Trp(O2)25, IsoAsp28] Exendin-4(1-39),
• des Pro36 [Met(O)14 Trp(O2)25, Asp28] Exendin-4(1-39),
• des Pro36 [Met(O)14 Trp(02)25, IsoAsp28] Exendin-4(1-39),
• wherein the group -Lys6-NH2 may be bound to the C-terminus of the Exendin-4 derivative;
• or an Exendin-4 derivative of the sequence
• H-(Lys)6-des Pro36 [Asp28] Exendin-4(1-39)-Lys6-NH2,
• des Asp28 Pro36, Pro37, Pro38Exendin-4(1-39)-NH2,
• H-(Lys)6-des Pro36, Pro38 [Asp28] Exendin-4(1-39)-NH2,
• H-Asn-(Glu)5des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-NH2,
• des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2,
• H-(Lys)6-des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2,
• H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2,
• H-(Lys)6-des Pro36 [Trp(02)25, Asp28] Exendin-4(1-39)-Lys6-NH2,
• H-des Asp28 Pro36, Pro37, Pro38 [Trp(02)25] Exendin-4(1-39)-NH2,
• H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-NH2,
• H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(02)25, Asp28] Exendin-4(1-39)-NH2,
• des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2,
• H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2,
• H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2,
• H-(Lys)6-des Pro36 [Met(O)14, Asp28] Exendin-4(1-39)-Lys6-NH2,
• des Met(O)14 Asp28 Pro36, Pro37, Pro38 Exendin-4(1-39)-NH2,
• H-(Lys)6-desPro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-NH2,
• H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-NH2,
• des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2,
• H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2,
• H-Asn-(Glu)5 des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2,
• H-Lys6-des Pro36 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-Lys6-NH2,
• H-des Asp28 Pro36, Pro37, Pro38 [Met(O)14, Trp(02)25] Exendin-4(1-39)-NH2,
• H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-NH2,
• H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Trp(02)25, Asp28] Exendin-4(1-39)-NH2,
• des Pro36, Pro37, Pro38 [Met(O)14, Trp(02)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2,
• H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(S1-39)-(Lys)6-NH2,
• H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2;
• or a pharmaceutically acceptable salt or solvate of any one of the afore-mentioned Exedin-4 derivative.
• Hormones are for example hypophysis hormones or hypothalamus hormones or regulatory active peptides and their antagonists as listed inRote Liste, ed. 2008, Chapter 50, such as Gonadotropine (Follitropin, Lutropin, Choriongonadotropin, Menotropin), Somatropine (Somatropin), Desmopressin, Terlipressin, Gonadorelin, Triptorelin, Leuprorelin, Buserelin, Nafarelin, Goserelin.
• A polysaccharide is for example a glucosaminoglycane, a hyaluronic acid, a heparin, a low molecular weight heparin or an ultra low molecular weight heparin or a derivative thereof, or a sulphated, e.g. a poly-sulphated form of the above-mentioned polysaccharides, and/or a pharmaceutically acceptable salt thereof. An example of a pharmaceutically acceptable salt of a poly-sulphated low molecular weight heparin is enoxaparin sodium.
• Pharmaceutically acceptable salts are for example acid addition salts and basic salts. Acid addition salts are e.g. HCl or HBr salts. Basic salts are e.g. salts having a cation selected from alkali or alkaline, e.g. Na+, or K+, or Ca2+, or an ammonium ion N+(R1)(R2)(R3)(R4), wherein R1 to R4 independently of each other mean: hydrogen, an optionally substituted C1-C6-alkyl group, an optionally substituted C2-C6-alkenyl group, an optionally substituted C6-C10-aryl group, or an optionally substituted C6-C10-heteroaryl group. Further examples of pharmaceutically acceptable salts are described in "Remington's Pharmaceutical Sciences" 17. ed. Alfonso R. Gennaro (Ed.), Mark Publishing Company, Easton, Pa., U.S.A., 1985and in Encyclopedia of Pharmaceutical Technology.
• Pharmaceutically acceptable solvates are for example hydrates.
• The delay mechanism may be employed with other types of auto-injectors. However, the delay mechanism is not restricted to use with auto-injectors. It may be likewise used with other mechanical equipment.
• The cap with the sheet metal spring may also be applied with other auto-injectors and injection devices.
• Further scope of applicability of the present invention will become apparent from the detailed description given hereinafter. However, it should be understood that the detailed description and specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.
Brief Description of the Drawings
• The present invention will become more fully understood from the detailed description given herein below and the accompanying drawings which are given by way of illustration only, and thus, are not limitive of the present invention, and wherein:

Figure 1

are two longitudinal sections of an auto-injector with a single compression spring for advancing a syringe with a needle, injecting a dose of medicament and retracting the syringe and needle, the auto-injector as-delivered,

Figure 2

are two longitudinal sections of the auto-injector with the syringe and needle advanced and the dose expelled from the syringe,

Figure 3

is a perspective sectional view of the auto-injector in the initial state offigure 1,

Figure 4

is another perspective sectional view of the auto-injector offigure 3, and

Figure 5

is a detail view of the distal end of the auto-injector with a delay mechanism and

Figure 6

is a detailed view of the proximal end of the Auto-injector showing the cap and needle shield remover.

• Corresponding parts are marked with the same reference symbols in all figures.
Detailed Description of Preferred Embodiments
• Figure 1 shows two longitudinal sections in different section planes of an auto-injector 1, the different section planes approximately 90° rotated to each other. The auto-injector 1 comprises anelongate housing 2. Asyringe 3, e.g. a Hypak syringe, with ahollow needle 4 is arranged in a proximal part of the auto-injector 1. When the auto-injector 1 or thesyringe 3 is assembled aprotective needle shield 5 is attached to theneedle 4. Astopper 6 is arranged for sealing thesyringe 3 distally and for displacing a liquid medicament M through thehollow needle 4. Thesyringe 3 is held in atubular syringe carrier 7 and supported at its proximal end therein. Asingle compression spring 8 is arranged in a distal part of the auto-injector 1. Aplunger 9 is arranged for forwarding the spring force of thecompression spring 8.
• Inside the housing 2 aretraction sleeve 10 is slidably arranged. Before the injection is triggered as shown infigure 1 theretraction sleeve 10 is in a maximum proximal position and prevented from moving in distal direction D by means ofstops 11 caught behind latches 12 in thehousing 2. A distal end of thecompression spring 8 bears against anend face 13 of theretraction sleeve 10. Due to thestops 11 and latches 12 the force of thecompression spring 8 is thus reacted into thehousing 2. The proximal end of thecompression spring 8 bears against adecoupling member 14 arranged around theplunger 9. Distally from theend face 13 the retraction sleeve has two or moreresilient arms 15 for holding astud 16 and keeping it from being moved in proximal direction P. Thestud 16 is arranged at the distal end of theplunger 9. Thestud 16 and theresilient arms 15 have corresponding ramp features for pushing theresilient arms 15 apart in order to allow thestud 16 and theplunger 9 to move in proximal direction P.
• Thedecoupling member 14 comprises athrust face 17 for bearing against a proximal end of thecompression spring 8. Proximally from the thrust face 17 two or moreresilient decoupling arms 18 are provided at thedecoupling member 14, thedecoupling arms 18 having inner ramped surfaces bearing against afirst shoulder 19 in theplunger 9 in proximal direction P. Theresilient decoupling arms 18 are supported by an inner wall of theretraction sleeve 10 in this situation so they cannot flex outward and slip past thefirst shoulder 19.
• Atrigger button 20 is arranged at the distal end D of the auto-injector 1. Thetrigger button 20 may be pushed in proximal direction P in order to start an injection. As long as thetrigger button 20 is not pushed theresilient arms 15 are caught between two ormore retainers 21 arranged at thetrigger button 20 so theresilient arms 15 cannot flex outward and thestud 16 although proximally biased by thecompression spring 8 cannot slip through.
• Thesyringe carrier 7 is engaged for joint axial movement with asyringe holder 22 which is slidably arranged in theretraction sleeve 10. Thesyringe holder 22 is provided with two or more resilientsyringe holder arms 23 arranged distally. Thesyringe holder arms 23 have a respective inclined surface for bearing against asecond shoulder 24 in theplunger 9 arranged proximally from thefirst shoulder 19. In the initial position shown infigure 1 thesyringe holder arms 23 are supported by an inner surface of thehousing 2 so they cannot flex outward and thesecond shoulder 24 cannot slip through. In order to support thesyringe holder arms 23 at the housing 2 a respective number of apertures are provided in theretraction sleeve 10.
• Figure 1 shows the auto-injector 1 as-delivered with acap 25 screwed onto to the proximal end P of the auto-injector 1.Figure 6 shows details of the proximal end P with thecap 25. Thecap 25 comprises asheet metal clip 26 with two ormore barbs 27 extending through an orifice into the proximal end P of the auto-injector 1. Thesheet metal clip 26 is mounted to thecap 25 for joint axial movement with respect to a longitudinal axis of the auto-injector 1. However, thesheet metal clip 26 may rotate independently from thecap 25. This may be achieved by attaching thesheet metal clip 26 with a hole in its base onto a pin protruding inwardly from thecap 25 and deforming the pin to form a mushroom-shapedclosing head 28 so as to prevent thesheet metal clip 26 from being removed while allowing some clearance for thesheet metal clip 26 to rotate. When thecap 25 is screwed onto the proximal P end of the auto-injector 1 thebarbs 27 are pushed down theprotective needle shield 5 and snap into a circumferential notch arranged in theprotective needle shield 5 or behind a shoulder thereof.
• When a user wants to operate the auto-injector 1 the first step is to unscrew thecap 25. Thus thebarbs 27 pull theprotective needle shield 5 off thesyringe 3 in proximal direction P and through the orifice making thesyringe 3 ready to be used.
• Asafety button 29 is arranged laterally at the distal part of thehousing 2. Thesafety button 29 serves for interlocking with thetrigger button 20 in a manner to prevent thetrigger button 20 from being inadvertently pushed without thesafety button 29 being pushed first.
• Consequently, in order to operate thetrigger button 20 thesafety button 29 has to be pushed transversally with respect to the longitudinal axis against the force of aspring element 30 which is formed in thesafety button 29. Thesafety button 29 is pivoted in the middle so pushing the proximal end of thesafety button 29 inward pulls aninterlock 31 at its proximal end obstructing thetrigger button 20 outward so thetrigger button 20 can be pushed.
• When thetrigger button 20 is pushed theretainers 21 are pushed in proximal direction P so theresilient arms 15 are allowed to flex outward. Under load of thecompression spring 8 the inclined surfaces of thestud 16 force theresilient arms 15 apart until thestud 16 can slip through.
• Thesecond shoulder 24 pushes thesyringe holder 22,syringe carrier 7 andsyringe 3 forward while no load is exerted onto thestopper 6. Thehollow needle 4 appears from the proximal end P and is inserted into an injection site, e.g. a patient's skin.
• The forward movement continues until thesyringe holder 22 bottoms out at afirst abutment 32 in the housing 2 (seefigure 2). The travel from the initial position (cf.figure 1) up to this point defines an injection depth, i.e. needle insertion depth.
• When thesyringe holder 22 has nearly bottomed out the resilientsyringe holder arms 23 have reached a widened portion 2.1 of thehousing 2 where they are no longer supported by the inner wall of thehousing 2. However, since the force required to insert theneedle 4 is relatively low thesecond shoulder 24 will continue to drive forward thesyringe holder 22 until proximal travel is halted at thefirst abutment 32. At this point thesyringe holder arms 23 are flexed out by the continued force of thesecond shoulder 24 and allow it to slip through. Now theplunger 9 no longer pushes against thesyringe holder 22 but against thestopper 6 for expelling the medicament M from thesyringe 3 and injecting it into or through the patient's skin.
• When thestopper 6 has nearly bottomed out in the syringe 3 (cf.figure 2) thedecoupling member 14 has reached a position where its protrusions push against thelatches 12 in a manner to decouple theretraction sleeve 10 from thehousing 2, so theretraction sleeve 10 may slide in distal direction D. Thus thecompression spring 8 is no longer grounded with its distal end in thehousing 2. Instead, as soon as thedecoupling member 14 has bottomed out at asecond abutment 33 the proximal end of thecompression spring 8 gets grounded in the housing while the distal end is pulling theretraction sleeve 10 in distal direction D.
• Just before thedecoupling member 14 decouples theretraction sleeve 10 from thehousing 2 thedecoupling arms 18 reach anaperture 34 in the retraction sleeve 10 (seefig. 4) so they are no longer kept from being flexed outward. Thedecoupling arms 18 are thus pushed outward by thefirst shoulder 19 pushing against its ramped surfaces so thefirst shoulder 19 slips through in distal direction as soon as thedecoupling member 14 has hit thesecond abutment 33.
• Thesyringe holder 22 is taken along in distal direction D by theretraction sleeve 10, e.g. by afront face 35. Thus thesyringe 3 andneedle 4 are retracted into a safe position inside thehousing 2, e.g. into the initial position. Theplunger 9, no longer bearing against thedecoupling arms 18 is pulled back too.
• In the distal part of the auto-injector 1 adelay mechanism 36 is arranged (seefigure 5 for details). Thedelay mechanism 36 comprises a circumferentialouter wall 37 with aback collar 38 attached to thehousing 2 and a circumferentialinner wall 39 with afront collar 40 attached to theretraction sleeve 10. A cavity between theouter wall 37 andinner wall 39 is filled with a viscous fluid, such as silicon grease. As theretraction sleeve 10 is moved in distal direction D theinner wall 39 glides along theouter wall 37 wherein theback collar 38 andfront collar 40 increasingly reduce the volume of the cavity. One or more orifices (not shown) provided in a part of thedelay mechanism 36 allow the viscous fluid to be pushed out of the cavity as the volume decreases. The force required to do this slows down the motion of theretraction sleeve 10.
• A circumferential shoulder 37.1 is arranged between two portions of theouter wall 37 with the two portions having different cross sections. Thus the cavity is sealed by thefront collar 40 only until thefront collar 40 reaches the shoulder 37.1. When thefront collar 40 has travelled past the shoulder 37.1 the cavity is rendered untight so the motion of theretraction sleeve 10 continues undamped from this point. Preferably this happens after thestopper 6 has bottomed out and after theplunger 9 has been decoupleddecoupling member 14.
• Theretraction sleeve 10 is released by thedecoupling member 14 from the housing 2 a certain amount of time or travel before thestopper 6 bottoms out in thesyringe 3 so that theapertures 34 of theretraction sleeve 10 and thedecoupling arms 18, which are now moving in opposite directions, meet after thestopper 6 andplunger 9 have stopped. The motion of theretraction sleeve 10 is slowed down by thedelay mechanism 36. Due to agap 41 between thefront face 35 and thesyringe holder 22 theretraction sleeve 10 is not yet dragging the syringe back in distal direction D. Theplunger 9 is still pushing against thestopper 6 and expelling residual medicament M. As thestopper 6 hits the proximal end of thesyringe 3 thestopper 6 andplunger 9 stop while theretraction sleeve 10 is still slowly moving back in distal direction D. Theapertures 34 now meet thedecoupling arms 18 allowing them to flex out and theplunger 9 to come clear. Theretraction sleeve 10 has now travelled back far enough to close thegap 41 so thesyringe holder 22,syringe carrier 7,syringe 3,needle 4 andplunger 9 are dragged back in distal direction D.
• Thecap 25 and thedelay mechanism 36 are not restricted to be used with the auto-injector 1 shown in the embodiments. Instead thecap 25 may be combined with any kind of auto-injector with the needle hidden in the housing prior to an injection. The delay mechanism (36) may be combined with any kind of auto-injector for ensuring full delivery of the syringe's contents and reliable triggering of the retraction, irrespective of the spring means or driving means used in the respective auto-injector.
• Thehousing 2 may have at least one viewing window for inspecting thesyringe 3.
• The auto-injector 1 may preferably be used for delivering one of an analgetic, an anticoagulant, insulin, an insulin derivate, heparin, Lovenox, a vaccine, a growth hormone, a peptide hormone, a proteine, antibodies and complex carbohydrates.
• Thedelay mechanism 36 may also be employed with other types of auto-injectors. However, thedelay mechanism 36 is not restricted to use with auto-injectors. It may be likewise used with other mechanical equipment.
• The aforementioned arrangement for coupling the plunger (9) to either, the syringe (3) or the stopper (6), may be applied in any auto-injector having a plunger for forwarding a force of a drive means to a syringe with a stopper. The primary advantage of this arrangement ensures the load from the drive means is not transferred directly to the stopper until the needle is inserted in the patient, thus avoiding a wet injection. The arrangement comprises the syringe holder (22) and associated syringe holder arms (23), a shoulder (e.g. the second shoulder 24) on the plunger (9), the support of the holder arms (23) by an inner surface in order to prevent them from flexing out in a first position and, a widened portion (2.1) for allowing them to flex radially and to disconnect from the plunger when in a more proximal position. The spring means or other drive means, the ability to retract the syringe or to forward a needle shroud after injection and other features described herein are not required for the prevention of a wet injection.
List of References

1

auto-injector

2

housing

2.1

widened portion

3

syringe

4

hollow needle

5

protective needle shield

6

stopper

7

syringe carrier

8

spring means, compression spring

8.1

distal end

8.2

proximal end

9

plunger

10

retraction sleeve

11

stop

12

latch

13

end face

14

decoupling member

15

resilient arm

16

stud

17

thrust face

18

decoupling arm

19

first shoulder

20

activating means, trigger button

21

retainer

22

syringe holder

23

syringe holder arm

24

second shoulder

25

cap

26

sheet metal clip

27

barb

28

closing head

29

safety button

30

spring element

31

interlock

32

first abutment

33

second abutment

34

aperture

35

front face

36

delay mechanism

37

outer wall

37.1

shoulder

38

back collar

39

inner wall

40

front collar

41

gap

D

distal end, distal direction

M

medicament

P

proximal end, proximal direction

Claims (11)

1. Auto-injector (1) for administering a dose of a liquid medicament (M), comprising:

   - an elongate housing (2) arranged to contain a syringe (3) with a hollow needle (4) and a stopper (6) for sealing the syringe (3) and displacing the medicament (M), the housing (2) having a distal end (D) and a proximal end (P) with an orifice intended to be applied against an injection site, wherein the syringe (3) is slidably arranged with respect to the housing (2),

   - driving means (8) capable of, upon activation:

   - pushing the needle (4) from a covered position inside the housing (2) into an advanced position through the orifice and past the proximal end (P) via a plunger (9),

   - operating the syringe (3) to supply the dose of medicament (M) via the plunger (9), and

   - retracting the syringe (3) with the needle (4) into the covered position after delivering the medicament (M),

   - a retraction sleeve (10), axially movably arranged in the housing (2),

   - at least one latch (12) for axially fixing the retraction sleeve (10) in a maximum proximal position,

   - a delay mechanism (36) for slowing down motion of the retraction sleeve (10) in distal direction, the delay mechanism (36) comprising a circumferential outer wall (37) with a back collar (38) attached to the housing (2) and a circumferential inner wall (39) with a front collar (40) attached to the retraction sleeve (10) wherein a cavity is defined between the outer wall (37) and inner wall (39), the cavity sealed by the back collar (38) against the inner wall (39) and by the front collar (40) against the outer wall (37), the cavity filled with a viscous fluid, wherein at least one orifice is arranged in the delay mechanism (36) for allowing the viscous fluid to be pushed out as the volume of the cavity decreases due to axial motion of the retraction sleeve (10) with respect to the housing (2)- at least one aperture (34) arranged in the retraction sleeve (10),

   wherein the latches (12) are arranged to be disengaged by the decoupling member (14) before the stopper (6) has reached a maximum proximal position in the syringe (3) when moved in proximal direction, wherein the apertures (34) are arranged to meet the decoupling arms (18) after the stopper (6) has reached its maximum proximal position by means of the motion of the retraction sleeve (10), wherein a decoupling member (14) is arranged to decouple the latch (12) when being moved in proximal direction (P) nearly into a maximum proximal position, thus allowing the retraction sleeve (10) to move in distal direction (D) and retract the needle (4), wherein the aperture (34) is arranged to allow a respective decoupling arm (18) of the decoupling member (14) to be flexed outward,characterized in that a gap (41) is provided between a front face (35) of the retraction sleeve (10) and a syringe holder (22) in their respective maximum proximal positions, wherein the syringe (4) is arranged for joint axial movement with the syringe holder, wherein the gap (41) is arranged to allow the retraction sleeve (10) to travel a distance before retracting the syringe holder (22) so the syringe holder (22) is retracted after the decoupling arms (18) met the apertures (34), wherein a circumferential shoulder is arranged between two portions of at least one of the inner wall and the outer wall with the two portions having different cross sections in a manner to have the cavity sealed by the respective collar (38, 40) only until the collar (38, 40) reaches the shoulder and rendering the cavity untight when the collar (38, 40) has travelled past the shoulder.
2. Auto-injector (1) according to claim 1,characterized in that the viscous fluid is silicone grease.
3. Auto-injector (1) according to one of the claims 1 to 2,characterized in that the driving means are arranged as spring means (8), wherein activating means (20) are arranged to lock the spring means (8) in a pressurized state prior to manual operation and capable of, upon manual operation, releasing the spring means (8) for injection.
4. Auto-injector (1) according to claim 3,characterized in that the spring means (8) is a single compression spring (8) arranged to be grounded at a distal end (8.1) in the housing (2) for advancing the needle (4) and for injecting the dose of medicament (M) and wherein the compression spring (8) is arranged to have its ground in the housing (2) switched to its proximal end (8.2) for retracting the syringe (3).
5. Auto-injector (1) according to claim 4,characterized in that the compression spring (8) is arranged inside the retraction sleeve (10) with its distal end bearing against a distal end face (13) and with its proximal end bearing against a thrust face (17) of the decoupling member (14).
6. Auto-injector (1) according to one of the claims 4 or 5,characterized in that the decoupling arms (18) have inner ramped surfaces bearing against a first shoulder (19) of the plunger (9) in proximal direction (P), wherein the resilient decoupling arms (18) are supportable by an inner wall of the retraction sleeve (10) in order to prevent the decoupling arms (18) from being flexed outward and slip past the first shoulder (19) and the aperture (34) in the retraction sleeve (10) allows the decoupling arms (18) to be flexed outward by the first shoulder (19) thus allowing the first shoulder (19) to slip through the decoupling arms (18) in proximal direction (P), wherein the plunger (9) is arranged for pushing the syringe (3) and/or the stopper (6) in proximal direction (P).
7. Auto-injector (1) according to claim 6,characterized in that the syringe holder (22) is slidably arranged in the retraction sleeve (10), wherein the syringe holder (22) is provided with at least two resilient syringe holder arms (23) arranged distally, the syringe holder arms (23) having a respective inclined surface for bearing against a second shoulder (24), which is arranged at the plunger (9) proximally from the first shoulder (19) wherein the syringe holder arms (23) are supportable by an inner surface of the housing (2) in order to prevent them from being flexed outward and wherein a widened portion (2.1) is provided in the housing (2) for allowing the syringe holder arms (23) to flex outwards when the syringe holder (22) has nearly reached a maximum proximal position thus allowing the second shoulder (24) to slip through the syringe holder arms (23) and to switch load of the compression spring (8) from the syringe (3) to the stopper (6).
8. Auto-injector (1) according to one of the claims 5 to 7,characterized in that a stud (16) is arranged at the distal end of the plunger (9), wherein the retraction sleeve (10) has two or more resilient arms (15) distally from the end face (13) for holding the stud (16), the stud (16) and/or the resilient arms (15) having ramp features so the resilient arms (15) may be pushed apart by the stud (16) when the plunger (9) is moved in proximal direction (P), wherein the activating means comprise a trigger button (20) arranged at the distal end (D) of the auto-injector (1), the trigger button (20) axially moveable and having at least two rigid retainers (21) for preventing the resilient arms (15) from being flexed outward when the trigger button (20) is in a maximum distal position and wherein, upon pushing the trigger button (20) in proximal direction (P) the retainers (21) are moved in proximal direction (P) in a manner to allow the resilient arms (15) to be flexed out by the stud (16) biased by the compression spring (8) in proximal direction (P) thus allowing the stud (16) to slip past the resilient arms (15) in proximal direction (P).
9. Auto-injector (1) according to claim 8,characterized in that a safety button (29) is arranged laterally at the housing (2), the safety button (29) having an interlock (31) for preventing the trigger button (20) from being pushed, the safety button (29) arranged to pull the interlock (31) outward when operated thus allowing the trigger button (20) to be pushed.
10. Auto-injector (1) according to one of the claims 1 to 9,characterized in that a cap (25) is provided at the proximal end (P) of the housing (2), wherein a sheet metal clip (26) is attached to the cap (25) for joint axial movement and independent rotation, the sheet metal clip (26) arranged to extend through an orifice into the housing (2) when the cap (25) is attached to the housing (2), wherein the sheet metal clip (26) comprises at least two barbs (27) snapped into a circumferential notch or behind a shoulder of a protective needle shield (5) attached to the hollow needle (4).
11. Auto-injector (1) according to claim 10,characterized in that the cap (25) is attachable to the housing (2) by a screw connection.

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